CN104860856B - A kind of method of alkali-free green syt isothiocyanates - Google Patents

A kind of method of alkali-free green syt isothiocyanates Download PDF

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CN104860856B
CN104860856B CN201510247148.XA CN201510247148A CN104860856B CN 104860856 B CN104860856 B CN 104860856B CN 201510247148 A CN201510247148 A CN 201510247148A CN 104860856 B CN104860856 B CN 104860856B
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isothiocyanates
alkali
carbon
primary amine
solvent
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CN104860856A (en
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李正义
张金龙
石嵩
郑崇谦
庄跃
殷乐
孙小强
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Changzhou University
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Changzhou University
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Abstract

A kind of method of alkali-free green syt isothiocyanates of the present invention, is related to organic chemical field.Carry out as steps described below：(1) using carbon sulfiding reagent and primary amine as raw material, solvent is added, organic reaction temperature is 100 DEG C~150 DEG C；Reaction time is 10~30 hours；The mol ratio of carbon sulfiding reagent and primary amine is 1:1.2‑3；(2) reaction terminate after, cooling, be spin-dried for, add dichloromethane, then with 10% watery hydrochloric acid extract and separate organic phase, washing, merge organic layer, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation, obtain isothiocyanates.It is of the invention only to need heating response in a solvent compared with preparation method of the prior art, alkali is added without extra, there is more environmental protection, with more preferable application value.

Description

A kind of method of alkali-free green syt isothiocyanates
Technical field
The present invention relates to organic chemical industry field, more particularly to a kind of method of alkali-free green syt isothiocyanates.
Background technology
Isothiocyanates is that a class has R-N=C=S structural compounds, is in the middle of a class purposes extremely wide organic synthesis Body and medicine intermediate, are widely used in the preparation of medicine, agricultural chemicals, dyestuff, therefore, the Study of synthesis method one of isothiocyanates It is directly an important topic of organic chemistry.
Before the present invention makes, the preparation method of isothiocyanates mainly has following several approach：
Thio phosgene synthetic method：Generation isothiocyanates, but the reaction are directly reacted by thio phosgene and aminated compounds Thio phosgene is needed to use, and thio phosgene is the volatile liquid of severe toxicity, it produces, transported and using all dangerous, to ring The harm in border is also larger.
Carbon disulfide method：First dithiocarbamates salt is formed in the presence of alkali by aminated compounds and carbon disulfide, then with Methylchloroformate, paratoluensulfonyl chloride, di-tert-butyl dicarbonate, solid phosgene, iodine, Clodronate ester, dicyclohexyl carbon two Target compound is made in imines or chlorosilane reaction.But it is harsh that these react big many conditions, needs substep to carry out, the reaction time compared with It is long, post-process cumbersome.
Rhodanate method：By halogenated hydrocarbons and rhodanide reaction generation isothiocyanates, but this method still suffers from many lack Fall into, such as target product yield is low, operating process is cumbersome and solvent load is very big.
Isonitrile method：In organic solvent, isothiocyanic acid is synthesized in the presence of metallic catalyst by isonitrile and sulphur powder or vulcanizing agent Ester, but the synthesis of isonitrile and purification dimension are big, and the toxicity of isonitrile is very big, thus also it is unfavorable for industrialized production.
Prepared in addition, the A of patent CN 101759614 are reported using formamide, sulfonic acid halide and elemental sulfur under base catalysis The method of isothiocyanates.But the acquisition of formamide and sulfonic acid halide is still inconvenient, and uneconomical.
Recently, we have reported two kinds and have acted on next step in alkali using carbon sulfiding reagent and primary amine as raw material (CN102503872A) or two steps (CN103102296B) synthesize isothiocyanates method.But both approaches still have a disadvantage End, that is, be required for additionally adding substantial amounts of alkali (excess), and wherein alkali participates in reacting respectively with hydrochloric acid and phenol into salt.
The content of the invention
It is in the prior art raw material in alkali effect synthesis isothiocyanates using carbon sulfiding reagent and primary amine that the present invention, which overcomes, Needing additionally to add a certain amount of alkali not enough, there is provided a kind of method of alkali-free green syt isothiocyanates.With phenoxy group sulphur Acyl chlorides or substituent phenoxy chlorosulfuric acid and primary amine are raw material one-step synthesis isocyanate derivative, need to only be heated in a solvent anti- Should, add alkali without extra.Reaction equation is as follows：
A kind of method of alkali-free green syt isothiocyanates, is carried out as steps described below：
(1) using carbon sulfiding reagent and primary amine as raw material, solvent is added, organic reaction temperature is 100 DEG C~150 DEG C；Reaction Time is 10~30 hours；The mol ratio of carbon sulfiding reagent and primary amine is 1:1.2-3；
(2) after reaction terminates, cooling is spin-dried for, and adds dichloromethane, then organic with 10% watery hydrochloric acid extract and separate Phase, washing merges organic layer, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation (ethyl acetate:Petroleum ether =1:5, volume ratio), obtain isothiocyanates.
Further, carbon sulfiding reagent used wherein in step (1) is phenoxy group chlorosulfuric acid or substituent phenoxy sulfonyl Chlorine,
Structural formula in wherein described substituent phenoxy chlorosulfuric acid isWherein substituent R1For The alkyl of 1-6 carbon atom, the alkoxy of 1-6 carbon atom, fluorine, chlorine, bromine or iodine atom, amino, substituted-amino, nitro；Its Middle substituent R1At the ortho position of phenoxy group chlorosulfuric acid, meta or para position.
Further, it is characterised in that the primary amine wherein described in step (1) is fats primary amine, aromatics primary amine, contained Alkylamine, aromatic amine, benzylamine, alpha substituted benzylamine, condensed ring amine or the heterocyclic aromatic amine of hetero atom or heterocycle.
Preferably, the heterocyclic aromatic amine wherein described in step (1) is aminopyrazole derivatives, amino furan derives Thing, aminothiophene derivative, aminopyridine derivative, amino-pyrazol-derivatives or aminoimidazole derivative.
Further, solvent for use is toluene, dimethylbenzene, chlorobenzene, DMF or two wherein in step (1) Methyl sulfoxide；Wherein solvent load is carbon sulfiding reagent：Solvent is 1:15(mmol/mL).
Preferably, solvent for use is toluene wherein in step (1).
Preferably, reaction temperature is 115 DEG C wherein in step (1)；Reaction time is 12~24 hours；Carbon sulfiding reagent Mol ratio with primary amine is 1:2.
Advantages of the present invention：Using phenoxy group chlorosulfuric acid or substituent phenoxy chlorosulfuric acid and primary amine as raw material, without extra Add one-step synthesis isocyanate derivative under conditions of alkali.Compared with the preparation method in document, with more green ring The advantage of guarantor, with more preferable application value.
Embodiment
The present invention will be described in detail with reference to embodiments, but the present invention is not limited to these embodiments.
Embodiment 1
Phenoxy group thioacid chloride (1mmol), 15ml toluene and aniline are sequentially added in 50ml single-necked flask (2mmol), 115 DEG C of heating stirrings react 16h.Stop reaction, cooling is spin-dried for, and 20ml dichloromethane is added, then with 10% Watery hydrochloric acid extract and separate organic phase, washing, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation (ethyl acetate: Petroleum ether=1:5) PITC, is obtained, yield is 80%.
1H NMR(500MHz,CDCl3)δ:7.35 (t, J=7.5Hz, 2H, ArH), 7.28 (d, J=7.5Hz, 1H, ArH), 7.23 (d, J=7.5Hz, 2H, ArH)；13C NMR(125MHz,CDCl3)δ:130.2,128.5,126.3,124.7,123.2； MS (70eV) m/z (%):135(M+,100).
Embodiment 2
With reference to the method for embodiment 1, so as to fluorophenoxy chlorosulfuric acid, as carbon sulfiding reagent, the yield of target product is 78%.
Embodiment 3
With reference to the method for embodiment 1, the mol ratio of phenoxy group chlorosulfuric acid and benzylamine is 1:1.2, the yield of target product is 61%.
Embodiment 4
With reference to the method for embodiment 1, the mol ratio of phenoxy group chlorosulfuric acid and benzylamine is 1:3, the yield of target product is 52%, rhenocure CA accessory substance (36%) can be produced.
Embodiment 5
With reference to the method for embodiment 1, using open-chain crown ether as reagent, react 12 hours, 4- methylisothiocyanate phenyl esters Yield be 86%.
1H NMR(500MHz,CDCl3)δ:7.13 (d, J=8.5Hz, 2H, ArH), 7.10 (d, J=8.5Hz, 2H, ArH), 2.34(s,3H,CH3)；13C NMR(125MHz,CDCl3)δ:137.5,134.4,130.1,128.4,125.5,21.2；MS (70eV) m/z (%):149(M+,100).
Embodiment 6
With reference to the method for embodiment 1, with 4-N, accelerine reacts 10 hours, 4-N, N- dimethyl as reagent The yield of phenyl isothiocyanate is 85%.
1H NMR(400MHz,CDCl3)δ:7.09 (d, J=8.8Hz, 2H, ArH), 6.59 (d, J=8.8Hz, 2H, ArH), 2.96(s,6H,CH3)；13C NMR(125MHz,CDCl3)δ:149.3,129.6,126.7,121.8,112.3,40.3；MS (70eV) m/z (%):178(M+,100).
Embodiment 7
With reference to the method for embodiment 1, using paranitroanilinum as reagent, react 30 hours, 4- nitro phenyl isothiocyanates Yield be 68%.
1H NMR(400MHz,CDCl3)δ:8.25 (d, J=8.8Hz, 2H, ArH), 7.35 (d, J=8.8Hz, 2H, ArH) ；13C NMR(100MHz,CDCl3)δ:145.9,140.5,138.0,126.4,125.3；MS (70eV) m/z (%):180(M+, 100).
Embodiment 8
With reference to the method for embodiment 1, using parachloroanilinum as reagent, react 24 hours, the production of 4- chlorine phenyl isothiocyanates Rate is 76%.
1H NMR(500MHz,CDCl3)δ:7.32 (d, J=8.5Hz, 2H, ArH), 7.16 (d, J=9.0Hz, 2H, ArH) ；13C NMR(125MHz,CDCl3)δ:136.7,132.9,130.0,129.8,126.9；MS (70eV) m/z (%):169(M+, 100).
Embodiment 9
With reference to the method for embodiment 1, using para-fluoroaniline as reagent, react 24 hours, the production of 4- fluorine phenyl isothiocyanates Rate is 71%.
1H NMR(500MHz,CDCl3)δ:7.22~7.19 (m, 2H, ArH), 7.04 (t, J=8.5Hz, 2H, ArH)；13CNMR(125MHz,CDCl3)δ:160.2,136.1,127.4,123.2,116.8；MS (70eV) m/z (%):153(M+, 100).
Embodiment 10
With reference to the method for embodiment 1, using benzylamine as reagent, react 12 hours, the yield of BITC is 83%.
1H NMR(500MHz,CDCl3)δ:7.39 (t, J=7.0Hz, 2H, ArH), 7.35 (d, J=7.0Hz, 1H, ArH), 7.31 (d, J=7.0Hz, 2H, ArH), 4.71 (s, 2H, CH2)；13C NMR(125MHz,CDCl3)δ:134.3,132.4, 129.0,128.4,126.8,48.7；MS (70eV) m/z (%):149(M+,28),91(100).
Embodiment 11
With reference to the method for embodiment 1, using naphthalidine as reagent, react 24 hours, the yield of 1- naphthalenylisothiocyanates For 78%.
1H NMR(500MHz,CDCl3)δ:8.10 (d, J=8.5Hz, 1H, ArH), 7.86 (d, J=8.0Hz, 1H, ArH), 7.78~7.75 (m, 1H, ArH), 7.62~7.54 (m, 2H, ArH), 7.42~7.38 (m, 2H, ArH)；13C NMR(125MHz, CDCl3)δ:136.1,134.0,129.3,128.4,127.7,127.5,127.4,127.1,125.4,123.4,122.7；MS (70eV) m/z (%):185(M+,100).
Embodiment 12
With reference to the method for embodiment 1, using n-hexylamine as reagent, react 12 hours, the yield of n-hexyl isothiocyanates For 83%.
1H NMR(500MHz,CDCl3)δ:3.52 (t, J=7.0Hz, 2H, NCH2), 1.73~1.67 (m, 2H, CH2), 1.45~1.39 (m, 2H, CH2), 1.37~1.29 (m, 4H, CH2), 0.91 (t, J=7.0Hz, 3H, CH3)；13C NMR (125MHz,CDCl3)δ:129.3,45.1,31.0,29.9,26.2,22.5,14.0；MS (70eV) m/z (%):143(M+, 10),115(100).
Embodiment 13
With reference to the method for embodiment 1, using cyclohexylamine as reagent, react 12 hours, the yield of cyclohexyl isothiocyanate For 88%.
1H NMR(500MHz,CDCl3)δ:3.71~3.69 (m, 1H, NCH), 1.94~1.86 (m, 2H, CH2), 1.74~ 1.64(m,4H,CH2), 1.51~1.38 (m, 4H, CH2)；13C NMR(125MHz,CDCl3)δ:129.5,55.4,33.2, 25.0,23.2；MS (70eV) m/z (%):141(M+,68),55(100)。

Claims (6)

1. a kind of method of alkali-free green syt isothiocyanates, it is characterised in that carry out as steps described below：
(1) using carbon sulfiding reagent and primary amine as raw material, solvent is added, organic reaction temperature is 100 DEG C~150 DEG C；Reaction time For 10~30 hours；The mol ratio of carbon sulfiding reagent and primary amine is 1:1.2-3,
Carbon sulfiding reagent used is phenoxy group chlorosulfuric acid or substituent phenoxy chlorosulfuric acid in step (1)；
(2) reaction terminate after, cooling, be spin-dried for, add dichloromethane, then with 10% watery hydrochloric acid extract and separate organic phase, water Wash, merge organic layer, saturated common salt water washing, anhydrous Na2SO4Dry, through column chromatography for separation, obtain isothiocyanates, it is described Ethyl acetate and petroleum ether volume ratio are 1 in chromatography:5.
2. the method for alkali-free green syt isothiocyanates according to claim 1, it is characterised in that wherein step (1) In used carbon sulfiding reagent be phenoxy group chlorosulfuric acid or substituent phenoxy chlorosulfuric acid,
Structural formula in wherein described substituent phenoxy chlorosulfuric acid isWherein substituent R1For 1-6 The alkyl of individual carbon atom, the alkoxy of 1-6 carbon atom, fluorine, chlorine, bromine or iodine atom, amino, substituted-amino, nitro；Wherein take For base R1At the ortho position of phenoxy group chlorosulfuric acid, meta or para position.
3. the method for alkali-free green syt isothiocyanates according to claim 1, it is characterised in that wherein step (1) Described in primary amine be fats primary amine, aromatics primary amine, benzylamine or alpha substituted benzylamine.
4. the method for alkali-free green syt isothiocyanates according to claim 1, it is characterised in that wherein step (1) Middle solvent for use is toluene, dimethylbenzene, chlorobenzene, N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Wherein solvent load is carbon sulphur Change reagent：Solvent is 1:15mmol/mL.
5. the method for alkali-free green syt isothiocyanates according to claim 4, it is characterised in that wherein step (1) Middle solvent for use is toluene.
6. a kind of method of alkali-free green syt isothiocyanates according to claim 1, it is characterised in that wherein step (1) reaction temperature is 115 DEG C in；Reaction time is 12~24 hours；The mol ratio of carbon sulfiding reagent and primary amine is 1:2.
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CN108503568A (en) * 2017-02-27 2018-09-07 无锡杰西医药股份有限公司 A kind of high-purity isosulfocyanate compound preparation method suitable for industrialized production
CN109503429A (en) * 2018-11-23 2019-03-22 山东汇海医药化工有限公司 A kind of method of raising N, N '-dicyclohexylcarbodiimide product purity
CN110845379A (en) * 2019-11-26 2020-02-28 刘科技 Preparation method of phenyl isothiocyanate derivative

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CN102503872A (en) * 2011-12-15 2012-06-20 常州大学 Method for preparing isothiocyanate
CN103102296B (en) * 2013-01-14 2014-12-17 常州大学 Method for synthesizing isothiocyanate by two steps
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